News from the FDA/CDC

FDA panel votes against 2 cancer indications but backs 4 of 6


Federal advisers have supported the efforts of pharmaceutical companies in four of six cases in which these firms are fighting to maintain cancer indications for approved drugs. The advisers voted against the companies in two cases.

The staff of the Food and Drug Administration will now consider these votes as they decide what to do regarding the six cases of what they have termed “dangling” accelerated approvals.

“One of the reasons I think we’re convening today is to prevent these accelerated approvals from dangling ad infinitum,” commented one of the members of the advisory panel.

In these cases, companies have been unable to prove the expected benefits that led the FDA to grant accelerated approvals for these indications.

These accelerated approvals, which are often based on surrogate endpoints, such as overall response rates, are granted on the condition that further findings show a clinical benefit – such as in progression-free survival or overall survival – in larger trials.

The FDA tasked its Oncologic Drugs Advisory Committee (ODAC) with conducting the review of the six accelerated approvals for cancer indications at a 3-day meeting (April 27-29).

These reviews were only for specific cancer indications and will not lead to the removal of drugs from the market. These drugs have already been approved for several cancer indications. For example, one of the drugs that was reviewed, pembrolizumab (Keytruda), is approved in the United States for 28 indications.

The FDA is facing growing pains in its efforts to manage the rapidly changing landscape for these immune checkpoint inhibitors. This field of medicine has experienced an “unprecedented level of drug development” in recent years, FDA officials said in briefing materials, owing in part to the agency’s willingness to accept surrogate markers for accelerated approvals. Although some companies have struggled with these, others have built strong cases for the use of their checkpoint inhibitors for these indications.

The ODAC panelists, for example, noted the emergence of nivolumab (Opdivo) as an option for patients with gastric cancer as a reason for seeking to withdraw an indication for pembrolizumab (Keytruda) for this disease.

Just weeks before the meeting, on April 16, the FDA approved nivolumab plus chemotherapy as a first-line treatment for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. This was a full approval based on data showing an overall survival benefit from a phase 3 trial.

Votes by indication

On April 29, the last day of the meeting, the ODAC panel voted 6-2 against maintaining pembrolizumab’s indication as monotherapy for an advanced form of gastric cancer. This was an accelerated approval (granted in 2017) that was based on overall response rates from an open-label trial.

That last day of the meeting also saw another negative vote. On April 29, the ODAC panel voted 5-4 against maintaining an indication for nivolumab in patients with hepatocellular carcinoma (HCC) who were previously treated with sorafenib (Nexavar).

This accelerated approval for nivolumab was granted in 2017. The FDA said it had requested ODAC’s feedback on this indication because of the recent full approval of another checkpoint inhibitor for HCC, atezolizumab (Tecentriq), in combination with bevacizumab (Avastin) for patients with unresectable or metastatic diseases who have not received prior systemic therapy. This full approval (in May 2020) was based on an overall survival benefit.

There was one last vote on the third day of the meeting, and it was positive. The ODAC panel voted 8-0 in favor of maintaining the indication for the use of pembrolizumab as monotherapy for patients with HCC who have previously been treated with sorafenib.

The FDA altered the composition of the ODAC panel during the week, adding members in some cases who had expertise in particular cancers. That led to different totals for the week’s ODAC votes, as shown in the tallies summarized below.

On the first day of the meeting (April 27), the ODAC panel voted 7-2 in favor of maintaining a breast cancer indication for atezolizumab (Tecentriq). This covered use of the immunotherapy in combination with nab-paclitaxel for patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1.

The second day of the meeting (April 28) also saw two positive votes. The ODAC panel voted 10-1 for maintaining the indication for atezolizumab for the first-line treatment of cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma, pending final overall survival results from the IMvigor130 trial. The panel also voted 5-3 for maintaining the indication for pembrolizumab in patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1.

The FDA is not bound to follow the voting and recommendations of its advisory panels, but it usually does so.


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